Inhalable formulation of a solution containing a tiotropium salt

ABSTRACT

A liquid, propellant-free pharmaceutical preparation comprising:  
     (a) a first active substance comprising a tiotropium salt, in a concentration based on tiotropium of between 0.0005% and 5% by weight;  
     (b) a second active substance selected from the group consisting of: an antiallergic, antihistamine, steroid, and leukotriene antagonist;  
     (c) a solvent selected from water or a water/ethanol mixture; and  
     (d) a pharmacologically acceptable preservative,  
     wherein the pH of the preparation is adjusted to between 2.0 and 4.5 with an acid and the tiotropium salt is dissolved in the solvent,  
     optionally including a pharmacologically acceptable complexing agent, stabilizer, a pharmacologically acceptable cosolvent, or other pharmacologically acceptable adjuvants and additives; a method for administering a pharmaceutical preparation by nebulizing the pharmaceutical preparation in an inhaler, and a method of treating asthma or COPD in a patient using the pharmaceutical preparation.

RELATED APPLICATIONS

[0001] Benefit under 35 U.S.C. §119(e) of prior provisional applicationSerial No. 60/253,613, filed Nov. 28, 2000, is hereby claimed.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to a propellant-free inhalableformulation of a pharmaceutically acceptable salt of tiotropiumdissolved in water or a mixture of water and ethanol, in conjunctionwith at least one other active substance preferably administered byinhalation, and propellant-free inhalable aerosols resulting therefrom.The formulation according to the invention is particularly suitable foradministering the active substance by inhalation, especially fortreating asthma and chronic obstructive pulmonary disease (COPD).

[0003] Tiotropium, chemically(1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^(2.4)]nonane,is known as tiotropium bromide from European Patent Application EP 418716 A1. The bromide salt of tiotropium has the following chemicalstructure:

[0004] The compound has valuable pharmacological properties and is knownby the name tiotropium bromide. Tiotropium and its salts are highlyeffective anticholinergics and can provide therapeutic benefit in thetreatment of asthma or COPD (chronic obstructive pulmonary disease). Themonohydrate of tiotropium bromide is also pharmacologically valuable.Both compounds are a preferred object of the present invention.

SUMMARY OF THE INVENTION

[0005] The present invention relates to liquid active substanceformulations of these compounds which can be administered by inhalation;the liquid formulations according to the invention have to meet highquality standards.

DESCRIPTION OF THE DRAWINGS

[0006]FIG. 1a shows a longitudinal section of the RESPIMAT® nebulizerdisclosed in WO 97/12687 through the atomizer with the spring undertension; and

[0007]FIG. 1b shows a longitudinal section of the RESPIMAT® nebulizerdisclosed in WO 97/12687 through the atomizer with the spring released.

[0008]FIGS. 1a and 1 b herein are identical to FIGS. 6a and 6b of WO97/12687.

DETAILED DESCRIPTION OF THE INVENTION

[0009] To achieve an optimum distribution of active substances in thelung, it makes sense to use a liquid formulation without propellantgases administered using suitable inhalers. Those inhalers which arecapable of nebulizing a small amount of a liquid formulation in thedosage needed for therapeutic purposes within a few seconds into anaerosol suitable for therapeutic inhalation are particularly suitable.Within the scope of the invention, preferred nebulizers are those inwhich an amount of less than 100 microliters, preferably less than 50microliters, most preferably less than 20 microliters of activesubstance solution can be nebulized preferably in one puff to form anaerosol having an average particle size of less than 20 microns,preferably less than 10 microns, so that the inhalable part of theaerosol already corresponds to the therapeutically effective quantity.

[0010] An apparatus of this kind for the propellant-free administrationof a metered amount of a liquid pharmaceutical composition forinhalation is described in detail, for example, in International PatentApplication WO 91/14468 “Atomizing Device and Methods” and also in WO97/12687, cf FIGS. 6a and 6b and the accompanying description. In anebulizer of this kind a pharmaceutical solution is converted by meansof a high pressure of up to 500 bar into an aerosol destined for thelungs, which is sprayed. Within the scope of the present specificationreference is expressly made to the entire contents of the literaturementioned above.

[0011] In inhalers of this kind, the formulations of solutions arestored in a reservoir. It is essential that the active substanceformulations used are sufficiently stable when stored and at the sametime are such that they can be administered directly, if possiblewithout any further handling, in accordance with their medical purpose.Moreover, they must not contain any ingredients which might interactwith the inhaler in such a way as to damage the inhaler or thepharmaceutical quality of the solution or of the aerosol produced.

[0012] To nebulize the solution, a special nozzle is used as described,for example, in WO 94/07607 or WO 99/16530, reference is expressly madehere to both these publications and each of which is incorporated hereinby reference in their entireties.

[0013] WO 98/27959 discloses formulations of solutions for the inhalerdescribed above which contain as additive the disodium salt of edeticacid (sodium edetate). For aqueous formulations of solutions which areto be converted into inhalable aerosols using the inhaler describedabove, the specification favors a minimum concentration of sodiumedetate of 50 mg/100 ml, in order to reduce the incidence of sprayanomalies. Among the Examples disclosed there is a formulationcontaining tiotropium bromide. In this formulation, the active substanceis dissolved in water. The proportion of sodium edetate is again 50mg/100 ml. Surprisingly, it has now been found

[0014] that formulations of solutions of tiotropium salts in water or awater-ethanol mixture wherein the proportion of the additive sodiumedetate is significantly less than 50 mg/100 ml show a reduction in thescattering of the composition delivered, compared with the formulationcontaining tiotropium bromide known from the prior art. In addition, thespray quality is very good. The resulting aerosol has very goodproperties for administration by inhalation.

[0015] Another advantage of the formulation is that, thanks to theabsence of or reduction in the additive sodium edetate in the activesubstance formulation, the pH of the solution formulation can belowered. Low pH levels are necessary for the long-term stability of thetiotropium salts in the formulation.

[0016] It is therefore an aim of the present invention to provide anaqueous active substance formulation containing a pharmaceuticallyacceptable tiotropium salt which meets the high standards needed inorder to be able to achieve optimum nebulization of a solution using theinhalers mentioned hereinbefore. The active substance formulationsaccording to the invention must be of sufficiently high pharmaceuticalquality, i.e., they should be pharmaceutically stable over a storagetime of some years, preferably at least one year, more preferably twoyears.

[0017] Another aim is to provide propellant-free formulations ofsolutions containing tiotropium salts which are nebulized under pressureusing an inhaler, the composition delivered by the aerosol producedfalling reproducibly within a specified range.

[0018] Another aim is to provide formulations of solutions withtiotropium and another active substance which can be administered byinhalation.

[0019] According to the invention, any pharmaceutically acceptable saltsof tiotropium may be used for the formulation. When the term tiotropiumsalt is used within the scope of the present invention, this is to betaken as a reference to tiotropium. According to the invention areference to tiotropium, which is the free ammonium cation, correspondsto a reference to tiotropium in the form of a salt (tiotropium salt)which contains an anion as counter-ion. Tiotropium salts which may beused within the scope of the present invention are preferably compoundswhich contain, in addition to tiotropium as counter-ion (anion),chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, and/ormethylsulfate.

[0020] Within the scope of the present invention tiotropium bromide ispreferred as the salt. References to tiotropium bromide within the scopeof the present invention must always be taken as references to allpossible amorphous and crystalline modifications of tiotropium bromide.These may for example contain molecules of solvent in their crystallinestructure. Of all the crystalline modifications of tiotropium bromidethose which also contain water (hydrates) are preferred according to theinvention. It is particularly preferred within the scope of the presentinvention to use tiotropium bromide monohydrate.

[0021] In the formulations according to the invention combinations witha tiotropium salt and only one other active substance are preferred.

[0022] In the formulations according to the invention, the tiotropiumsalts are dissolved in a solvent. The solvent may be exclusively water,or it may be a mixture of water and ethanol. Ethanol may be added to theformulation in order to increase the solubility of additives or otheractive substances apart from the tiotropium salt, preferably tiotropiumbromide or tiotropium bromide monohydrate. The relative proportion ofethanol to water is not limited; it may be 90% by volume, for example.Preferably, the maximum limit of ethanol is 70% by volume, particularly60% by volume and most preferably 30% by volume. The remaining % byvolume consist of water. The preferred solvent is water without theaddition of ethanol.

[0023] The concentration of the tiotropium salt based on the proportionof tiotropium in the finished pharmaceutical preparation depends on thetherapeutic effect sought. For most of the complaints which respond totiotropium the concentration of tiotropium is between 0.0005% and 5% byweight, preferably between 0.001% and 3% by weight.

[0024] The pH of the formulation according to the invention is between2.0 and 4.5, preferably between 2.5 and 3.5 and more preferably between2.7 and 3.5 and particularly preferably between 2.7 and 3.2. Mostpreferred are pHs with an upper limit of 3.1.

[0025] The pH is adjusted by the addition of pharmacologicallyacceptable acids.

[0026] Examples of inorganic acids which are preferred for this purposeinclude: hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, and/or phosphoric acid.

[0027] Examples of particularly suitable organic acids are: ascorbicacid, citric acid, malic acid, tartaric acid, maleic acid, succinicacid, fumaric acid, acetic acid, formic acid, and/or propionic acid,etc. Preferred inorganic acids are hydrochloric acid and sulfuric acid.It is also possible to use acids which form an acid addition salt withthe active substance or, in the case of combined preparations, with oneof the active substances.

[0028] Of the organic acids, ascorbic acid, fumaric acid and citric acidare preferred, especially citric acid. If desired, mixtures of theabovementioned acids may also be used, particularly in the case of acidswhich have other properties in addition to their acidifying properties,e.g., those which act as flavorings or antioxidants, such as for examplecitric acid or ascorbic acid. Hydrochloric acid deserves special mentionas a preferred inorganic acid.

[0029] If desired, pharmacologically acceptable bases may be used totitrate the pH precisely. Suitable bases include for example alkalimetal hydroxides and alkali metal carbonates. The preferred alkali ionis sodium. If bases of this kind are used, care must be taken to ensurethat the resulting salts, which are then contained in the finishedpharmaceutical formulation, are pharmacologically compatible with theabovementioned acid.

[0030] According to the invention, there is no need to add edetic acid(EDTA) or one of the known salts thereof, sodium edetate, to the presentformulation as a stabilizer or complexing agent.

[0031] Another preferred embodiment contains edetic acid and/or thesalts thereof.

[0032] In a preferred embodiment with sodium edetate the content basedon sodium edetate is less than 10 mg/100 ml. In this case, there is onepreferred range from 5 mg/100 ml to less than 10 mg/100 ml or anotherfrom greater than 0 to 5 mg/100 ml.

[0033] In another embodiment the content of sodium edetate is 10 to 30mg/100 ml, preferably not more than 25 mg/100 ml.

[0034] In a preferred embodiment this additive is omitted entirely.

[0035] The remarks made concerning sodium edetate also apply analogouslyto other comparable additives which have complexing properties and canbe used instead, such as for example nitrilotriacetic acid and the saltsthereof.

[0036] By complexing agents is preferably meant within the scope of thepresent invention molecules which are capable of entering into complexbonds. Preferably, these compounds should have the effect of complexingcations, most preferably metal cations.

[0037] The other active substances apart from the tiotropium salt in thecombined preparation are selected in particular from among theantihistamines, antiallergic agents, leukotriene antagonists and/orsteroids.

[0038] These active substances include:

[0039] As steroids: alclometasone, alclometasone dipropionate,alisactide, amcinonide, aminoglutethimide, aristocort diacetate,beclomethasone, beclomethasone-17,21-dipropionate, betamethasonevalerate, betamethasone adamantoate, budesonide, butixocort,canesten-HC, ciclometasone, clobetasol, clobetasone, cloprednol,cloprednol, fluocortin butyl, cortivazol, deflazacort, deflazacort,demetex, deprodone, deprodone propionate, dexamethasone,dexamethasone-21-isonicotinate, dexamethasone isonicotinate,diflorasone, difluprednate, endrisone, fluazacort, flucloroloneacetonide, flunisolide, fluocinolone acetonide, fluocinonide,fluocortin, fluocortolone caproate, fluodexan, fluorometholone,fluticasone, fluticasone propionate, formebolone, formocortal,halcinonide, halometasone, halopredone acetate, hydrocortisone,hydrocortisone-17-butyrate, hydrocortisone aceponate, hydrocortisonebutyrate propionate, icomethasone enbutate, lotrisone, mazipredone,medrysone, meprednisone, methylprednisolone aceponate, mometasone,mometasone furoate, mycophenolate mofetil, pranlukast, paramethasoneacetate, prednicarbate, promedrol, seratrodast, tipredan, tixocortolpivalate, triamcinolone, triamcinolone hexacetonide, trilostane,triamcinolone benetonide, ulobetasol propionate, zileuton, and methyl9-α-chloro-6-α-fluoro-11-β-17-α-dihydroxy-16-α-methyl-3-oxo-1,4-androstadiene-17-β-carboxylate-17-propionate.

[0040] Particularly preferred are the combinations of tiotropiumbromide, or tiotropium bromide-monohydrate and budesonide, flunisolide,beclomethasone dipropionate or fluticasone, as well as thepharmacologically acceptable (possibly other) salts thereof.

[0041] The preferred combination comprises tiotropium bromide, ortiotropium bromide monohydrate and budesonide.

[0042] If the combined formulation contains a leukotriene antagonist,this is preferably selected from among montelukast, pranlukast,zafirlukast,1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropaneacetic acid,1-(((R)-3-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid or[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid. Montelukast, pranlukast and/or zafirlukast are preferred.

[0043] The concentration of the leukotriene antagonist is from 0.05 wt.% to 10 wt. %, preferably up to 5 wt. %, more preferably 0.1 wt. % to3.5 wt. %.

[0044] The following are mentioned as examples of antihistamines andantiallergic agents: azelastine, astemizole, bamipine, carbinoxaminehydrogen maleate, cetirizine, dexchlorpheniramine, chlorphenoxamine,clemastine, clemastine hydrogen fumarate, desloratadine, dimenhydrinate,dimethindene, disodium cromoglycate, diphenhydramine, doxylamine,ebastine, emedastine, epinastine, fexofenadine, ketotifen,levocabastine, loratadine, meclozine, mequitazine, mizolastine,nedocromil, pheniramine, and promethazine. Epinastine, nedocromil,disodium cromoglycate, astemizole, mequitazine, carbinoxamine, andclemastine, and the corresponding pharmaceutically acceptable salts arepreferred.

[0045] In the combined preparation, the concentration of theantiallergic agents and/or antihistamines is preferably 0.05 wt. % to 15wt. %, preferably up to 10 wt. %, more preferably 0.1 wt. % to 10 wt. %,most preferably 0.1 wt. % to 7 wt. %.

[0046] All the abovementioned active substances may optionally also beused in the form of their pharmacologically acceptable salts thereof.

[0047] The combined preparations are preferably formulations in whichtiotropium is present in solution. The other active substance may bedissolved or suspended; this is generally determined by the other activesubstance and the particular solvent used.

[0048] If the additional active substance is one which is vulnerable atlow pHs, it is preferably formulated as a suspension. The advantage of asuspended form is that the pH can be made more acidic, which is to thebenefit of the stability of the dissolved tiotropium. The preferred pHrange of tiotropium bromide is between 2.0 and 4.5, preferably 2.5 and3.5, most preferably between 2.7 and 3.2.

[0049] In the case of steroids, these are preferably used in suspendedform, especially fluticasone. This is particularly true if the solventused is only water without ethanol. If ethanol is added, the steroid mayalso be formulated as a solution. However, it has been found thatbudesonide, for example, is also sufficiently stable at a pH of 3.5 ifit is dissolved in a mixture of water and ethanol.

[0050] With regard to the use of the formulations according to theinvention in the inhaler described within the scope of the presentinvention, it may be advantageous if all the ingredients of theformulation are present in solution.

[0051] As well as ethanol, other cosolvents and/or other adjuvants maybe added to the formulation according to the invention.

[0052] Other preferred cosolvents are those which contain hydroxylgroups or other polar groups, for example, alcohols, especiallyisopropyl alcohol, glycols—especially propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylenealcohols, and polyoxyethylene fatty acid esters.

[0053] By adjuvants and additives are meant, in this context, anypharmacologically acceptable and therapeutically useful substance whichis not an active substance, but can be formulated together with theactive substance(s) in the pharmacologically suitable solvent, in orderto improve the qualities of the active substance formulation.Preferably, these substances have no pharmacological effects or noappreciable or at least no undesirable pharmacological effects in thecontext of the desired therapy. The adjuvants and additives include, forexample, surfactants such as, e.g., soya lecithin, oleic acid, sorbitanesters such as sorbitan trioleate, polyvinylpyrrolidone, otherstabilizers, complexing agents, antioxidants and/or preservatives whichprolong the shelf life of the finished pharmaceutical formulation,flavorings, vitamins and/or other additives known in the art. Theadditives also include pharmacologically acceptable salts such as sodiumchloride, for example.

[0054] Suitable surfactants or suspension-stabilizing agents include allthe pharmacologically acceptable substances which have a lipophilichydrocarbon group and one or more functional hydrophilic groups,especially C₅₋₂₀-fatty alcohols, C₅₋₂₀-fatty acids, C₅₋₂₀-fatty acidesters, lecithin, glycerides, propyleneglycol esters, polyoxyethylenes,polysorbates, sorbitan esters and/or carbohydrates. C₅₋₂₀-fatty acids,propyleneglycol diesters and/or triglycerides and/or sorbitans of theC₅₋₂₀-fatty acids are preferred, while oleic acid and sorbitan mono-,di- or trioleates are particularly preferred. Alternatively,toxicologically and pharmaceutically acceptable polymers and/or blockpolymers may be used as suspension stabilizing agents.

[0055] The quantity of surfactant may be up to 1:1 based on theproportion by weight of the suspended active substances; amounts of0.0001:1 to 0.5:1 are preferred while amounts of from 0.0001:1 to 0.25:1are especially preferred.

[0056] The preferred excipients include antioxidants such as ascorbicacid, for example, provided that it has not already been used to adjustthe pH, vitamin A, vitamin E, tocopherols and similar vitamins orprovitamins occurring in the human body.

[0057] Preservatives can be added to protect the formulation fromcontamination with pathogenic bacteria. Suitable preservatives are thoseknown from the prior art, particularly benzalkonium chloride or benzoicacid or benzoates, such as sodium benzoate, in the concentration knownfrom the prior art.

[0058] Preferred formulations contain only benzalkonium chloride, anacid for adjusting the pH and sodium edetate, in addition to the solventwater and/or water/ethanol and the tiotropium salt.

[0059] In another preferred embodiment, sodium edetate is omitted. Theseembodiments may optionally also contain sodium chloride.

[0060] As already mentioned a number of times, tiotropium bromide isdescribed in EP 418 716 A1 and crystalline tiotropium bromidemonohydrate may be obtained using a process which is described in moredetail below.

[0061] In order to prepare the crystalline monohydrate according to thepresent invention, the tiotropium bromide obtained by the methoddisclosed in EP 418 716 A1, for example, first has to be taken up inwater, heated, purified with activated charcoal and, after removal ofthe activated charcoal, the tiotropium bromide-monohydrate is slowlycrystallized while cooling slowly.

[0062] The following procedure is preferably followed:

[0063] In a reaction vessel of suitable dimensions, the solvent is mixedwith tiotropium bromide, which has been obtained by the method disclosedin EP 418 716 A1, for example.

[0064] For each mole of tiotropium bromide put in, 0.4 to 1.5 kg,preferably 0.6 to 1 kg, most preferably about 0.8 kg of water are usedas solvent.

[0065] The mixture obtained is heated with stirring, preferably to above50° C., most preferably to above 60° C. The maximum temperature whichcan be selected is determined by the boiling point of the solvent used.Preferably, the mixture is heated to a range from 80° C. to 90° C.Activated charcoal, either dry or moistened with water, is added to thissolution. Preferably, 10 g to 50 g, more preferably 15 g to 35 g, mostpreferably about 25 g of activated charcoal are put in per mol oftiotropium bromide used. If desired the activated charcoal is suspendedin water before being added to the solution containing tiotropiumbromide. 70 g to 200 g, preferably 100 g to 160 g, more preferably about135 g of water are used, per mol of tiotropium bromide put in, in orderto suspend the activated charcoal. If the activated charcoal issuspended in water beforehand, before being added to the solutioncontaining tiotropium bromide, it is advisable to rinse again with thesame amount of water. After the activated charcoal has been added,stirring is continued at constant temperature for between 5 minutes and60 minutes, preferably between 10 minutes and 30 minutes, morepreferably for about 15 minutes and the mixture obtained is filtered toremove the activated charcoal. The filter is then rinsed with water. 140g to 400 g, preferably 200 g to 320 g, most preferably about 270 g ofwater are used for this, per mol of tiotropium bromide used. Thefiltrate is then slowly cooled, preferably to a temperature of 20° C. to25° C. The cooling preferably takes place at a cooling rate of 1 to 10°C. every 10 to 30 minutes, preferably 2° C. to 8° C. every 10 to 30minutes, more preferably 3° C. to 5° C. every 10 to 20 minutes, mostpreferably 3° C. to 5° C. about every 20 minutes. If desired, thecooling to 20° C. to 25° C. may be followed by further cooling to below20° C., more preferably to 10° C. to 15° C. After cooling is complete,stirring is continued for between 20 minutes and 3 hours, preferablybetween 40 minutes and 2 hours, more preferably for about one hour tocomplete the crystallization. The crystals obtained are then isolated byfiltering or suction filtering to remove the solvent. If it should provenecessary to subject the crystals obtained to a further washing step, itis advisable to use water or acetone as the washing solvent. 0.1 L to1.0 L, preferably 0.2 L to 0.5 L, more preferably about 0.3 L of solventmay be used per mol of tiotropium bromide put in, in order to wash thetiotropium bromide monohydrate crystals obtained. If necessary thewashing step may be repeated. The product obtained is dried in vacuo orusing circulating heated air until a water content of 2.5% to 4.0% isobtained.

[0066] According to one aspect the present invention therefore alsorelates to formulations of solutions of the type described above usingcrystalline tiotropium bromide monohydrate which may be obtained by theprocedure described above.

[0067] The pharmaceutical formulations containing tiotropium saltsaccording to the invention are preferably used in an inhaler of the kinddescribed hereinbefore in order to produce the propellant-free aerosolsaccording to the invention. At this point we should once again expresslymention the patent documents described hereinbefore, to which referenceis hereby made.

[0068] As described at the beginning, a further developed embodiment ofthe preferred inhaler is disclosed in WO 97/12687 and FIG. 6 thereof.This nebulizer (RESPIMAT®) can advantageously be used to produce theinhalable aerosols according to the invention containing a tiotropiumsalt as active substance. Because of its cylindrical shape and handysize of less than 9 cm to 15 cm long and 2 cm to 4 cm wide, the devicecan be carried anywhere by the patient. The nebulizer sprays a definedvolume of the pharmaceutical formulation out through small nozzles athigh pressures, so as to produce inhalable aerosols.

[0069] The preferred atomizer essentially consists of an upper housingpart, a pump housing, a nozzle, a locking clamp, a spring housing, aspring and a storage container, characterized by

[0070] a pump housing fixed in the upper housing part and carrying atone end a nozzle body with the nozzle or nozzle arrangement,

[0071] a hollow piston with valve body,

[0072] a power take-off flange in which the hollow body is fixed andwhich is located in the upper housing part,

[0073] a locking clamping mechanism located in the upper housing part,

[0074] a spring housing with the spring located therein, which isrotatably mounted on the upper housing part by means of a rotarybearing,

[0075] a lower housing part which is fitted onto the spring housing inthe axial direction.

[0076] The hollow piston with valve body corresponds to a devicedisclosed in WO 97/12687. It projects partially into the cylinder of thepump housing and is disposed to be axially movable in the cylinder.Reference is made particularly to FIGS. 1 to 4, especially FIG. 3, andthe associated parts of the description. At the moment of release of thespring the hollow piston with valve body exerts, at its high pressureend, a pressure of 5 MPa to 60 MPa (about 50 to 600 bar), preferably 10MPa to 60 MPa (about 100 to 600 bar) on the fluid, the measured amountof active substance solution. Volumes of 10 to 50 microliters arepreferred, volumes of 10 to 20 microliters are more preferable, whilst avolume of 15 microliters per actuation is particularly preferred.

[0077] The valve body is preferably mounted at the end of the hollowpiston which faces the nozzle body.

[0078] The nozzle in the nozzle body is preferably microstructured,i.e., produced by micro-engineering. Microstructured nozzle bodies aredisclosed for example in WO 94/07607; reference is hereby made to thecontents of this specification, especially FIG. 1 and the associateddescription, and which is incorporated herein by reference in itsentirety.

[0079] The nozzle body consists for example of two sheets of glassand/or silicon securely fixed together, at least one of which has one ormore microstructured channels which connect the nozzle inlet end to thenozzle outlet end. At the nozzle outlet end there is at least one roundor non-round opening 2 microns to 10 microns deep and 5 microns to 15microns wide, the depth preferably being 4.5 microns to 6.5 microns andthe length being 7 microns to 9 microns.

[0080] If there are a plurality of nozzle openings, preferably two, thedirections of spraying of the nozzles in the nozzle body may runparallel to each other or may be inclined relative to one another in thedirection of the nozzle opening. In the case of a nozzle body having atleast two nozzle openings at the outlet end, the directions of sprayingmay be inclined relative to one another at an angle of 20° to 160°,preferably at an angle of 60° to 150°, most preferably 80° to 100°.

[0081] The nozzle openings are preferably arranged at a spacing of 10microns to 200 microns, more preferably at a spacing of 10 microns to100 microns, still more preferably 30 microns to 70 microns. A spacingof 50 microns is most preferred.

[0082] The directions of spraying therefore meet in the region of thenozzle openings. As already mentioned, the liquid pharmaceuticalpreparation hits the nozzle body at an entry pressure of up to 600 bar,preferably 200 bar to 300 bar and is atomized through the nozzleopenings into an inhalable aerosol. The preferred particle sizes of theaerosol are up to 20 microns, preferably 3 microns to 10 microns.

[0083] The locking clamping mechanism contains a spring, preferably acylindrical helical compression spring as a store for the mechanicalenergy. The spring acts on the power take-off flange as a spring memberthe movement of which is determined by the position of a locking member.The travel of the power take-off flange is precisely limited by an upperstop and a lower stop. The spring is preferably tensioned via astepping-up gear, e.g., a helical sliding gear, by an external torquewhich is generated when the upper housing part is turned relative to thespring housing in the lower housing part. In this case, the upperhousing part and the power take-off flange contain a single- ormulti-speed spline gear.

[0084] The locking member with the engaging locking surfaces is arrangedin an annular configuration around the power take-off flange. Itconsists for example of a ring of plastics or metal which is inherentlyradially elastically deformable. The ring is arranged in a planeperpendicular to the axis of the atomizer. After the locking of thespring, the locking surfaces of the locking member slide into the pathof the power take-off flange and prevent the spring from being released.The locking member is actuated by means of a button. The actuatingbutton is connected or coupled to the locking member. In order toactuate the locking clamping mechanism the actuating button is movedparallel to the annular plane, preferably into the atomizer, and thedeformable ring is thereby deformed in the annular plane. Details of theconstruction of the locking clamping mechanism are described in WO97/20590.

[0085] The lower housing part is pushed axially over the spring housingand covers the bearing, the drive for the spindle and the storagecontainer for the fluid.

[0086] When the atomizer is operated, the upper part of the housing isrotated relative to the lower part, the lower part taking the springhousing with it. The spring meanwhile is compressed and biased by meansof the helical sliding gear, and the clamping mechanism engagesautomatically. The angle of rotation is preferably a whole-numberfraction of 360°, e.g., 180°. At the same time as the spring istensioned, the power take-off component in the upper housing part ismoved along by a given amount, the hollow piston is pulled back insidethe cylinder in the pump housing, as a result of which some of the fluidfrom the storage container is sucked into the high pressure chamber infront of the nozzle.

[0087] If desired, a plurality of replaceable storage containerscontaining the fluid to be atomized can be inserted in the atomizer oneafter another and then used. The storage container contains the aqueousaerosol preparation according to the invention.

[0088] The atomizing process is initiated by gently pressing theactuating button. The clamping mechanism then opens the way for thepower take-off component. The biased spring pushes the piston into thecylinder in the pump housing. The fluid emerges from the nozzle of theatomizer in the form of a spray.

[0089] Further details of the construction are disclosed in PCTapplications WO 97/12683 and WO 97/20590, to which reference is herebymade and each of which is incorporated herein by reference in theirentireties.

[0090] The components of the atomizer (nebulizer) are made of a materialsuitable for their function. The housing of the atomizer and, if thefunction allows, other parts as well are preferably made of plastics,e.g., by injection moulding. For medical applications, physiologicallyacceptable materials are used.

[0091]FIGS. 1a/b, which are identical to FIGS. 6a/b of WO 97/12687, showthe RESPIMAT® nebulizer with which the aqueous aerosol preparationsaccording to the invention can advantageously be inhaled.

[0092]FIG. 1a shows a longitudinal section through the atomizer with thespring under tension, and FIG. 1b shows a longitudinal section throughthe atomizer with the spring released.

[0093] The upper housing part (51) contains the pump housing (52), onthe end of which is mounted the holder (53) for the atomizer nozzle. Inthe holder is the nozzle body (54) and a filter (55). The hollow piston(57) fixed in the power take-off flange (56) of the locking clampingmechanism projects partly into the cylinder of the pump housing. At itsend the hollow piston carries the valve body (58). The hollow piston issealed off by the gasket (59). Inside the upper housing part is the stop(60) on which the power take-off flange rests when the spring isrelaxed. Located on the power take-off flange is the stop (61) on whichthe power take-off flange rests when the spring is under tension. Afterthe tensioning of the spring, the locking member (62) slides between thestop (61) and a support (63) in the upper housing part. The actuatingbutton (64) is connected to the locking member. The upper housing partends in the mouthpiece (65) and is closed off by the removableprotective cap (66).

[0094] The spring housing (67) with compression spring (68) is rotatablymounted on the upper housing part by means of the snap-fit lugs (69) androtary bearings. The lower housing part (70) is pushed over the springhousing. Inside the spring housing is the replaceable storage container(71) for the fluid (72) which is to be atomized. The storage containeris closed off by the stopper (73), through which the hollow pistonprojects into the storage container and dips its end into the fluid(supply of active substance solution).

[0095] The spindle (74) for the mechanical counter is mounted on theoutside of the spring housing. The drive pinion (75) is located at theend of the spindle facing the upper housing part. On the spindle is theslider (76).

[0096] The nebulizer described above is suitable for nebulizing theaerosol preparations according to the invention to form an aerosolsuitable for inhalation.

[0097] If the formulation according to the invention is nebulized usingthe method described above (RESPIMAT®), the mass expelled, in at least97%, preferably at least 98% of all the actuations of the inhaler(puffs), should correspond to a defined quantity with a range oftolerance of not more than 25%, preferably 20% of this quantity.Preferably, between 5 mg and 30 mg, more preferably between 5 mg and 20mg of formulation are delivered as a defined mass per puff.

[0098] The proportion of the mass delivered which is outside a tolerancelimit of not more than 25% in relation to the desired mass should beless than 1.5%, preferably less than 1.2%.

[0099] However, the formulation according to the invention can also benebulized using inhalers other than those described above, for examplejet-stream inhalers.

EXAMPLES

[0100] I. Example of the Synthesis of Tiotropium Bromide Monohydrate

[0101] 15.0 kg of tiotropium bromide are added to 25.7 kg of water in asuitable reaction vessel. The mixture is heated to 80° C. to 90° C. andstirred at constant temperature until a clear solution is formed.Activated charcoal (0.8 kg), moistened with water, is suspended in 4.4kg of water, this mixture is added to the solution containing tiotropiumbromide and rinsed with 4.3 kg of water. The mixture thus obtained isstirred for at least 15 minutes at 80° C. to 90° C. and then filteredthrough a heated filter into an apparatus which has been preheated to anouter temperature of 70° C. The filter is rinsed with 8.6 kg of water.The contents of the apparatus are cooled to a temperature of 20° C. to25° C. at a rate of 3° C. to 5° C. every 20 minutes. Using cold water,the apparatus is cooled further to 10° C. to 15° C. and crystallizationis completed by stirring for at least another hour. The crystals areisolated using a suction filter drier, the crystal slurry isolated iswashed with 9 L of cold water (10° C. to 15° C.) and cold acetone (10°C. to 15° C.). The crystals obtained are dried at 25° C. for 2 hours ina nitrogen current. Yield: 13.4 kg of tiotropium bromide monohydrate(86% of theory). TABLE 1 Pharmaceutical Formulations 100 g ofPharmaceutical Preparation Contains the Following Amounts TiotropiumTiotropium pH, Bromide Bromide Benzalkonium Sodium Adjusted Example(Based on Monohydrate (Based Chloride Edetate with HCl No. Tiotropium)(g) on Tiotropium) (g) (mg) (mg) (1N) 1 0.099 — 10 25 3.0 2 0.006 — 1025 3.0 3 0.099 — 10 10 3.0 4 0.006 — 10 10 3.0 5 — 0.099 10 25 3.0 6 —0.006 10 25 3.0 7 — 0.099 10 10 3.0 8 — 0.006 10 10 3.0

Examples 9 to 12 Budesonide

[0102] Each of Examples 1 to 8 may additionally contain:

[0103] Example 9a: budesonide: 0.3 g, pH, adjusted with HCl: 3.0,solvent water only, no ethanol;

[0104] Example 9b: budesonide: 0.3 g, pH, adjusted with HCl: 3,5;

[0105] Example 9c: budesonide: 0.3 g, pH, adjusted with HCl: 4.0;

[0106] Example 10: analogous to Example 9a to 9c with budesonide: 0.6 g,

[0107] Example 11: analogous to Example 9a to 9c with budesonide: 1.3 g,

[0108] Example 12: analogous to Example 9a to 9c with budesonide: 2.0 g.

[0109] In Examples 9 to 12 the steroid is present in the formulation insuspension. Sorbitan trioleate may be used as a surfactant.

Examples 13 to 15

[0110] Analogous to Examples 9 to 12. Benzalkonium chloride is exchangedfor sodium benzoate.

[0111] Examples 16 to 19

[0112] Analogous to Examples 9 to 12. Instead of hydrochloric acid,citric acid is exclusively used to adjust the pH.

Examples 20 to 30

[0113] The ingredients and amounts are analogous to Examples 9 to 19.Instead of water, a mixture of water (10 vol. %) and ethanol (90 vol. %)is used. Budesonide is present in solution.

Example 31

[0114] Epinastine: 0.2 g;

[0115] EDTA: 25 mg;

[0116] Tiotropium bromide monohydrate: 29 mg;

[0117] 0.1 N hydrochloric acid to adjust the pH to 3.0; and

[0118] water to 100 ml.

Other Examples

[0119] Analogously to Examples 9 to 30 described above, the same amountof flunisolide, beclomethasone dipropionate, or fluticasone is usedinstead of budesonide. In the case of fluticasone, lecithin ispreferably added instead of sorbitan trioleate in the case of thesuspension formulation. The steroids are formulation as a suspension ifthe solvent used is water on its own. In the case of a mixture of waterand ethanol, the steroid may be in solution.

We claim:
 1. A liquid, propellant-free pharmaceutical preparationcomprising: (a) a first active substance comprising a tiotropium salt,in a concentration based on tiotropium of between 0.0005% and 5% byweight; (b) a second active substance selected from the group consistingof: an antiallergic, antihistamine, steroid, and leukotriene antagonist;(c) a solvent selected from water or a water/ethanol mixture; and (d) apharmacologically acceptable preservative, wherein the pH of thepreparation is adjusted to between 2.0 and 4.5 with an acid and thetiotropium salt is dissolved in the solvent, optionally including apharmacologically acceptable complexing agent, stabilizer, apharmacologically acceptable cosolvent, or other pharmacologicallyacceptable adjuvants and additives.
 2. The pharmaceutical preparationaccording to claim 1, wherein the tiotropium salt is a salt formed withHBr, HCl, HI, monomethylsulfuric acid ester, methanesulfonic acid, orp-toluenesulfonic acid.
 3. The pharmaceutical preparation according toclaim 1, wherein the active substance is tiotropium bromide.
 4. Thepharmaceutical preparation according to claim 1, wherein the activesubstance is tiotropium bromide monohydrate.
 5. The pharmaceuticalpreparation according to claim 1, wherein the solvent is water.
 6. Thepharmaceutical preparation according to claim 2, wherein the solvent iswater.
 7. The pharmaceutical preparation according to claim 3, whereinthe solvent is water.
 8. The pharmaceutical preparation according toclaim 4, wherein the solvent is water.
 9. The pharmaceutical preparationaccording to claim 1, wherein the solvent is a water-ethanol mixturewith up to 90 vol. % of ethanol.
 10. The pharmaceutical preparationaccording to claim 2, wherein the solvent is a water-ethanol mixturewith up to 90 vol. % of ethanol.
 11. The pharmaceutical preparationaccording to claim 3, wherein the solvent is a water-ethanol mixturewith up to 90 vol. % of ethanol.
 12. The pharmaceutical preparationaccording to claim 4, wherein the solvent is a water-ethanol mixturewith up to 90 vol. % of ethanol.
 13. The pharmaceutical preparationaccording to claim 9, wherein the solvent is a water-ethanol mixturewith up to 70 vol. % of ethanol.
 13. The pharmaceutical preparationaccording to claim 9, wherein the solvent is a water-ethanol mixturewith up to 60 vol. % of ethanol.
 14. The pharmaceutical preparationaccording to claim 13, wherein the solvent is a water-ethanol mixturewith up to 30 vol. % of ethanol.
 15. The pharmaceutical preparationaccording to one of claims 1 to 4, wherein the pharmaceuticalpreparation does not contain a complexing agent.
 16. The pharmaceuticalpreparation according to one of claims 1 to 4, wherein thepharmaceutical preparation does not contain a stabilizer.
 17. Thepharmaceutical preparation according to one of claims 1 to 4, whereinedetic acid salt is present in an amount of greater than 0 up to 25mg/100 ml.
 18. The pharmaceutical preparation according to claim 17,wherein edetic acid salt is present in an amount of from 5 to less than10 mg/100 ml.
 19. The pharmaceutical preparation according to claim 17,wherein the edetic acid salt is sodium edetate.
 20. The pharmaceuticalpreparation according to one of claims 1 to 4, wherein the pH is between2.5 and 3.5.
 21. The pharmaceutical preparation according to claim 20,wherein the pH is between 2.7 and 3.3.
 22. The pharmaceuticalpreparation according to claim 21, wherein the pH is between 2.7 and3.0.
 23. The pharmaceutical preparation according to one of claims 1 to4, wherein the concentration based on tiotropium is between 0.0005% and5% by weight.
 24. The pharmaceutical preparation according to claim 23,wherein the concentration based on tiotropium is between 0.001% to 3% byweight.
 25. The pharmaceutical preparation according to one of claims 1to 4, wherein the pharmacologically acceptable preservative isbenzalkonium chloride.
 26. The pharmaceutical preparation according toone of claims 1 to 4, wherein the pharmaceutical preparation comprises apharmacologically acceptable adjuvant or additive.
 27. Thepharmaceutical preparation according to claim 26, whereinpharmacologically acceptable adjuvant or additive is an antioxidant. 28.The pharmaceutical preparation according to one of claims 1 to 4,wherein the pharmaceutical preparation contains no cosolvents and/orpharmacologically acceptable adjuvants and additives apart from thepreservative.
 29. The pharmaceutical preparation according to one ofclaims 1 to 4, wherein the tiotropium salt is present in a concentrationbased on tiotropium of between 0.001% and 3% by weight;
 30. Thepharmaceutical preparation according to one of claims 1 to 4, whereinthe tiotropium salt is present in a concentration based on tiotropium ofbetween 0.001% and 0.1% by weight;
 31. The pharmaceutical preparationaccording to one of claims 1 to 4, wherein the ingredients are dissolvedin the solvent.
 32. The pharmaceutical preparation according to one ofclaims 1 to 4, wherein the second active substance is in suspension inthe solvent.
 33. The pharmaceutical preparation according to one ofclaims 1 to 4, wherein the second active substance is a steroid.
 34. Thepharmaceutical preparation according to claim 33, wherein theconcentration of the steroid is 0.05 wt. % to 5 wt. %.
 35. Thepharmaceutical preparation according to claim 33, wherein the steroid isselected from the group consisting of: budesonide, beclomethasonedipropionate, fluticasone, and flunisolide.
 36. The pharmaceuticalpreparation according to one of claims 1 to 4, wherein the second activesubstance is an antiallergic or an antihistamine.
 37. The pharmaceuticalpreparation according to claim 36, wherein the concentration of theantiallergic or the antihistamine is 0.05 wt. % to 15 wt. %.
 38. Thepharmaceutical preparation according to claim 36, wherein theantiallergic or the antihistamine is selected from the group consistingof: epinastine, nedocromil, disodium cromoglycate, astemizole,mequitazine, carbinoxamine, and clemastine, or a correspondingpharmaceutically acceptable salt thereof.
 39. The pharmaceuticalpreparation according to one of claims 1 to 4, wherein the second activesubstance is a leukotriene antagonist.
 40. The pharmaceuticalpreparation according to claim 39, wherein the concentration of theleukotriene antagonist is 0.05 wt. % to 10 wt. %.
 41. The pharmaceuticalpreparation according to claim 39, wherein the leukotriene antagonist isselected from the group consisting of: montelukast, pranlukast,zafirlukast,1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-aceticacid, and1-(((R)-3-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-aceticacid,[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid.
 42. A pharmaceutical preparation according to claim 1, wherein thepharmaceutical preparation comprises: water as the solvent; asurfactant; 0.1 wt. % of tiotropium bromide; a second active substanceselected from the group consisting of: antiallergics, antihistamines,steroids, and leukotriene antagonists; 0.01 wt. % of benzalkoniumchloride; and 0.05 wt. % of sodium edetate, wherein the pH of thepreparation is adjusted to 3.0 with hydrochloric acid or citric acid.43. A method for administering a pharmaceutical preparation according toone of claims 1 to 4, comprising nebulizing the pharmaceuticalpreparation in an inhaler selected from the group consisting of: (a) aninhaler according to WO 91/14468, or (b) an inhaler according to FIGS.6a and 6b of WO 97/12687.
 44. A method for administering apharmaceutical preparation according to one of claims 1 to 4, comprisingnebulizing the pharmaceutical preparation in an inhaler which nebulizesdefined amounts of the pharmaceutical preparation by the application ofpressures from 100 to 600 bar through a nozzle having at least onenozzle opening with a depth of 2 to 10 microns and a width of 5 to 15microns to form an inhalable aerosol.
 45. The method according to claim44, wherein at least one nozzle opening is at least two nozzle openingswhich are inclined relative to one another in the direction of thenozzle opening at an angle of from 20 degrees to 160 degrees.
 46. Themethod according to claim 44, wherein the defined amounts of thepharmaceutical preparation are 10 to 50 microliters.
 47. The methodaccording to claim 43, wherein the inhaler is 9 cm to 15 cm long and 2cm to 4 cm wide.
 48. The method according to claim 44, wherein theinhaler is 9 cm to 15 cm long and 2 cm to 4 cm wide.
 49. The methodaccording to claim 43, wherein the mass of pharmaceutical formulationdelivered in at least 97% of all actuations of the inhaler is between 5mg and 30 mg within a range of tolerance of 25%.
 50. The methodaccording to claim 44, wherein the mass of pharmaceutical formulationdelivered in at least 97% of all actuations of the inhaler is between 5mg and 30 mg within a range of tolerance of 25%.
 51. The methodaccording to claim 43, wherein the mass of pharmaceutical formulationdelivered in at least 97% of all actuations of the inhaler is between 5mg and 30 mg within a range of tolerance of 20%.
 52. The methodaccording to claim 44, wherein the mass of pharmaceutical formulationdelivered in at least 97% of all actuations of the inhaler is between 5mg and 30 mg within a range of tolerance of 20%.
 53. The methodaccording to claim 43, wherein the mass of pharmaceutical formulationdelivered in at least 98% of all actuations of the inhaler is between 5mg and 30 mg within a range of tolerance of 20%.
 54. The methodaccording to claim 44, wherein the mass of pharmaceutical formulationdelivered in at least 98% of all actuations of the inhaler is between 5mg and 30 mg within a range of tolerance of 20%.
 55. A method oftreating asthma or COPD in a patient, the method comprisingadministering to the patient a pharmaceutical preparation according toone of claims 1 to
 4. 56. A method of treating asthma or COPD in apatient, the method comprising administering to the patient apharmaceutical preparation using the method of claim
 43. 57. A method oftreating asthma or COPD in a patient, the method comprisingadministering to the patient a pharmaceutical preparation using themethod of claim
 44. 58. A method for administering a pharmaceuticalpreparation according to claim 26, comprising nebulizing thepharmaceutical preparation in an inhaler selected from the groupconsisting of: (a) an inhaler according to WO 91/14468, or (b) aninhaler according to FIGS. 6a and 6b of WO 97/12687.
 59. A method foradministering a pharmaceutical preparation according to claim 26,comprising nebulizing the pharmaceutical preparation in an inhaler whichnebulizes defined amounts of the pharmaceutical preparation by theapplication of pressures from 100 to 600 bar through a nozzle having atleast one nozzle opening with a depth of 2 to 10 microns and a width of5 to 15 microns to form an inhalable aerosol.
 60. A method foradministering a pharmaceutical preparation according to claim 28,comprising nebulizing the pharmaceutical preparation in an inhalerselected from the group consisting of: (a) an inhaler according to WO91/14468, or (b) an inhaler according to FIGS. 6a and 6b of WO 97/12687.61. A method for administering a pharmaceutical preparation according toclaim 28, comprising nebulizing the pharmaceutical preparation in aninhaler which nebulizes defined amounts of the pharmaceuticalpreparation by the application of pressures from 100 to 600 bar througha nozzle having at least one nozzle opening with a depth of 2 to 10microns and a width of 5 to 15 microns to form an inhalable aerosol. 62.A method for administering a pharmaceutical preparation according toclaim 33, comprising nebulizing the pharmaceutical preparation in aninhaler selected from the group consisting of: (a) an inhaler accordingto WO 91/14468, or (b) an inhaler according to FIGS. 6a and 6b of WO97/12687.
 63. A method for administering a pharmaceutical preparationaccording to claim 33, comprising nebulizing the pharmaceuticalpreparation in an inhaler which nebulizes defined amounts of thepharmaceutical preparation by the application of pressures from 100 to600 bar through a nozzle having at least one nozzle opening with a depthof 2 to 10 microns and a width of 5 to 15 microns to form an inhalableaerosol.
 64. A method for administering a pharmaceutical preparationaccording to claim 36, comprising nebulizing the pharmaceuticalpreparation in an inhaler selected from the group consisting of: (a) aninhaler according to WO 91/14468, or (b) an inhaler according to FIGS.6a and 6b of WO 97/12687.
 65. A method for administering apharmaceutical preparation according to claim 36, comprising nebulizingthe pharmaceutical preparation in an inhaler which nebulizes definedamounts of the pharmaceutical preparation by the application ofpressures from 100 to 600 bar through a nozzle having at least onenozzle opening with a depth of 2 to 10 microns and a width of 5 to 15microns to form an inhalable aerosol.
 66. A method for administering apharmaceutical preparation according to claim 39, comprising nebulizingthe pharmaceutical preparation in an inhaler selected from the groupconsisting of: (a) an inhaler according to WO 91/14468, or (b) aninhaler according to FIGS. 6a and 6b of WO 97/12687.
 67. A method foradministering a pharmaceutical preparation according to claim 39,comprising nebulizing the pharmaceutical preparation in an inhaler whichnebulizes defined amounts of the pharmaceutical preparation by theapplication of pressures from 100 to 600 bar through a nozzle having atleast one nozzle opening with a depth of 2 to 10 microns and a width of5 to 15 microns to form an inhalable aerosol.
 68. A method foradministering a pharmaceutical preparation according to claim 41,comprising nebulizing the pharmaceutical preparation in an inhalerselected from the group consisting of: (a) an inhaler according to WO91/14468, or (b) an inhaler according to FIGS. 6a and 6b of WO 97/12687.69. A method for administering a pharmaceutical preparation according toclaim 41, comprising nebulizing the pharmaceutical preparation in aninhaler which nebulizes defined amounts of the pharmaceuticalpreparation by the application of pressures from 100 to 600 bar througha nozzle having at least one nozzle opening with a depth of 2 to 10microns and a width of 5 to 15 microns to form an inhalable aerosol. 70.A method of treating asthma or COPD in a patient, the method comprisingadministering to the patient a pharmaceutical preparation using themethod of claim
 58. 71. A method of treating asthma or COPD in apatient, the method comprising administering to the patient apharmaceutical preparation using the method of claim
 59. 72. A method oftreating asthma or COPD in a patient, the method comprisingadministering to the patient a pharmaceutical preparation using themethod of claim
 60. 73. A method of treating asthma or COPD in apatient, the method comprising administering to the patient apharmaceutical preparation using the method of claim
 61. 74. A method oftreating asthma or COPD in a patient, the method comprisingadministering to the patient a pharmaceutical preparation using themethod of claim
 62. 75. A method of treating asthma or COPD in apatient, the method comprising administering to the patient apharmaceutical preparation using the method of claim
 63. 76. A method oftreating asthma or COPD in a patient, the method comprisingadministering to the patient a pharmaceutical preparation using themethod of claim
 64. 77. A method of treating asthma or COPD in apatient, the method comprising administering to the patient apharmaceutical preparation using the method of claim
 65. 78. A method oftreating asthma or COPD in a patient, the method comprisingadministering to the patient a pharmaceutical preparation using themethod of claim
 66. 79. A method of treating asthma or COPD in apatient, the method comprising administering to the patient apharmaceutical preparation using the method of claim
 67. 80. A method oftreating asthma or COPD in a patient, the method comprisingadministering to the patient a pharmaceutical preparation using themethod of claim
 68. 81. A method of treating asthma or COPD in apatient, the method comprising administering to the patient apharmaceutical preparation using the method of claim 69.